UMIT-2 - Adaptive Phase IIb Platform Trial to Determine the Efficacy and Safety of Therapeutics for CCHF (UMIT-2)

UMIT-2: A Randomized, Multi-country, Adaptive Phase IIb Platform Trial to Determine the Efficacy and Safety of Therapeutics for Crimean-Congo Haemorrhagic Fever

CCHF has a wide geographical distribution with cases mainly occurring in Asia, the Middle East, South-Eastern Europe and Africa. Since its emergence in 2002, Turkiye has been the epicentre of activity worldwide reporting up to more than 1000 cases annually. CCHF case management relies on the provision of optimised supportive care; therapeutic options lack a robust evidence base

The UMIT-2 Trial (UMIT = 'Hope' in Turkish) will be the first large randomised controlled trial of novel therapeutics in CCHF, undertaken in multiple trial sites in Turkiye and Iraq. It uses an efficient adaptive platform design (Phase IIb), focussed on antiviral efficacy with interim monitoring to introduce new arms and allow early stopping for futility, efficacy, or safety

Study Overview

• Status: Not yet recruiting
• Conditions: Crimean-Congo Hemorrhagic Fever
• Intervention / Treatment: Other: Optimised Standard of Care; Drug: Favipiravir; Drug: Ribavin

Detailed Description

This will be a 1:1:1 randomised open-label phase 2b trial of Favipiravir (IV & PO) and Ribavirin (IV & PO) vs optimised standard of care in CCHF aimed at evaluating virological efficacy. This is an adaptive multi-arm Phase II platform for patients with CCHF. Key design features are:

Treatment arms can be added or removed.

Shared standard of care (SoC, control) arm so that a greater proportion of more patients receive experimental therapeutics. Eligibility to randomisation to specific treatment arms is based on treatment specific inclusion/exclusion criteria and all comparisons to SoC are within the same eligibility set and concurrent randomisation.

Timing of interim analyses flexible to make use of the seasonality of CCHF to ensure they take place during low recruitment periods.

• Study Type: Interventional
• Enrollment (Estimated): 378
• Phase: Phase 2

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Adult in-patients (≥18 years)

Laboratory confirmed CCHF infection by positive polymerase chain reaction (PCR) test within 5 days prior to randomisation

Capacity to provide informed consent signed by study patient or legally acceptable representative (for illiterate individuals).

Women of childbearing potential (WOCBP) and male patients who are sexually active with WOCBP must agree to use a highly effective method of contraception (as outlined in section 5.4 below) from the first administration of trial treatment, throughout trial treatment and for the duration outlined in trial protocol as well as addition 14 days for women and 7 days for men after the last dose of trial treatment.

Severity Grading System (SGS) for CCHF - mild/moderate.

Less than or equal to 7 days from onset of CCHF symptoms

Willingness to participate in the full protocol

Requirement to be hospitalised for treatment-

Exclusion Criteria:

Stage 4 severe chronic kidney disease or requiring dialysis (i.e., estimated glomerular filtration (eGFR) rate <30 mL/min/1.73 m2)

Pregnant or breast feeding

Anticipated transfer to another hospital which is not a study site within 72 hours

Known Allergy to any study medication

Patients participating in another clinical trial of an investigational medicinal product (CTIMP) within the last 30 days.

Previous intolerance of Favipiravir or Ribavirin

Any participants deemed not suitable, based on investigators opinion.

Patients taking the drugs listed below within 30 days or 5 times the half-life (whichever is longer) of enrolment:

Pyrazinamide: Pyrazinamide administration with favipiravir examined possible renal urate transporter interactions. Pyrazinamide increased blood uric acid levels 2 to 9 mg/dL over baseline. The addition of favipiravir increased blood uric acid levels 4 to 11 mg/dL over baseline, indicating a moderate additive effect.

Repaglinide: Favipiravir administration with repaglinide, an anti-diabetic agent that is extensively metabolized by CYP2C8 and CYP3A4, increased repaglinide plasma AUC 30 to 50% due to inhibition of CYP2C8.

Theophylline: Theophylline administration with favipiravir increases plasma Cmax and AUC of favipiravir through xanthine oxidase (XO) interaction. The primary metabolite of theophylline is known to be metabolized by XO which is partially involved in metabolism of favipiravir.

Famciclovir, Sulindac: Famciclovir and Sulindac are converted to active metabolite by Aldehyde Oxidase (AO). Favipiravir inhibits AO and decrease the concentration of active metabolite of Famciclovir and Sulindac.

Paracetamol: Coadministration of paracetamol (650 mg once daily) and favipiravir (1200 mg twice daily or 800 mg twice daily) increased paracetamol Cmax and AUC by 3% and 16% (1200 mg doses) and by 8% and 14% (800 mg doses). In the UMIT-2 trial after screening and randomisation the daily dose of paracetamol in adults should be no more than 3000 mg/day (rather than 4000 mg/day) -

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Optimised standard of care (oSOC); Optimised standard of care will include treatment per national guidelines for CCHF case management in Turkiye and Iraq, and any other supportive medication or therapies as required. The standard of care arm will exclude any medicine defined as investigation arms of this study. Any supportive medication or therapies will be recorded on the patient CRFs.	Other: Optimised Standard of Care; Optimised standard of care will include treatment per national guidelines for CCHF case management in Turkiye and Iraq, and any other supportive medication or therapies as required.
Active Comparator: Arm B: Favipiravir; Day 1 (First 24 hours): IV Favipiravir 2600 mg twice daily (BD) Day 2 (24-48 hours): IV Favipiravir 1200 mg twice daily (BD) Day 3 -7 (Post 48 hours): Oral (PO) Favipiravir 1200 mg twice daily (BD)1 until hospital discharge up to 7 days (14 doses) whichever is soonest. Plus any additional supportive care deemed necessary by the study investigator	Drug: Favipiravir; 6-fluoro-3-hydroxypyrazine-2-carboxamide, T-705
Active Comparator: Arm C: Ribavirin; Day 1 (First 24 hours): IV Ribavirin (33mg/kg) loading dose followed by IV Ribavirin 16mg/kg every 6 hours Day 2 (24-48 hours): IV Ribavirin 16mg/kg four times daily (QDS) Days 3-5: Oral (PO) Ribavirin 16mg/kg four times daily (QDS) Days 6 -7: Oral (PO) Ribavirin 8mg/kg four times daily (QDS) until hospital discharge Plus any additional supportive care deemed necessary by the study investigator	Drug: Ribavin; 1-3,4-dihydroxy-5-1,2,4-triazole-3-carboxamide

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Virologic objective: To compare CCHFV viral dynamics of investigational therapeutics relative to the control arm	Comparison of CCHFV viral load clearance by Day 5 for treatment arms compared to Standard of Care arm.	Day 5 from treatment start

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety Objective: To determine the safety and tolerability of investigational therapeutics relative to the control arm	Comparison of incidence of serious adverse events in treatment arms compared to standard of care arm. Comparison of the frequency and characterisation of clinically significant adverse events related to study agent administration (Safety and Tolerability of Favipiravir and Ribavirin CTCAE v5 Grade ≥3 adverse events)	Day 29
Clinical Objective: To compare time to successful hospital discharge between participants receiving investigational therapeutics, relative to the control arm	Time from Randomisation to discharge from hospital	Day 29
Antiviral Objective: To evaluate antiviral efficacy of investigational therapeutics (1)	Comparison of CCHFV viral load reduction between for treatment arms compared to Standard of Care arm	Day 10
Antiviral Objective: To evaluate antiviral efficacy of investigational therapeutics (2)	Comparison of Viral load reduction by PCR test for treatment arms compared to Standard of Care arm	Day 10
Safety Objective: To compare the overall mortality in patients with CCHF who receive different investigational therapeutics with those who receive the control arm	Mortality at Days 14 and 28 (time from date of randomisation to death) for treatment arms compared to Standard of Care arm	Day 28
Safety Objective: To compare mortality rates among patients whose baseline predictors of disease place them in different categories for disease severity, who receive different investigational therapeutics.	Mortality at Days 14 and 28 (time from date of randomisation to death) in different SGS groups for treatment arms compared to Standard of Care arm	Day 28
Pharmacokinetic objective:To characterise the plasma pharmacokinetics (PK) of therapeutics in CCHF	To investigate the exposure-response relationship of Favipiravir on CCHF viral dynamics by analysing concentrations of investigation therapeutics in plasma	Day 29

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
To characterise virus, host immune response and viral resistance over time	Change in host immune response, CCHFV culture and sequencing related to study agent administration	Day 29

Collaborators and Investigators

• Sponsor: Liverpool School of Tropical Medicine

Study record dates

Study Major Dates

• Study Start (Estimated): July 1, 2025
• Primary Completion (Estimated): December 30, 2027
• Study Completion (Estimated): August 31, 2028

Study Registration Dates

• First Submitted: February 13, 2025
• First Submitted That Met QC Criteria: March 4, 2025
• First Posted (Actual): March 25, 2025

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: March 4, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Keywords: Favipiravir; Ribavirin; CCHF; Crimean Congo Hemorrhagic Fever
• Additional Relevant MeSH Terms: Vector Borne Diseases; Infections; RNA Virus Infections; Virus Diseases; Arbovirus Infections; Tick-Borne Diseases; Body Temperature Changes; Bunyaviridae Infections; Fever; Hemorrhagic Fevers, Viral; Hemorrhagic Fever, Crimean; Anti-Infective Agents; Antiviral Agents; Favipiravir
• Other Study ID Numbers: 25-013 (Other Identifier: Institutional Review Board, Jianan Psychiatric Center, MOHW)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No